Dialkylaminoalkyl esters of piperazine carboxylic acids



Patented Nov. 11, 1952 DIALKYLAMINOALKYHESWERSEOF PIPERAZINE CARBOXYLIQJAGIDS f Richard J Turner; Somerville, N. J., assignor to 1 American Cyanamid Company, New XQ k, N. .Y i .-a corporation of Maine No Drawing; Application -flctobelrz1; 11.949,

7 Serial No. 122,865

. 7,0laims.

The present invention relates to substituted piperazines. More particularly, it relates to dialkylaminoethyl esters of-=piperazine'-l carboxylic "ac-ids; their salts and methods of, preparing'i'the "same.

" f'I-he dialkylaminoethyl "'piperazin'el t-carboxylates "of the presentinvention may be illustrated by the following general formula:

in which R,.is hydrogen. orlan. @aIKyL; aralkyl orarylradical,RJlis-a:lowenalkyl radicaloffrom 1 to v4lcarbon.atoms .andlX and Yware; hydrogen orv lower alkyl radicals.

In general, the compounds of the present .invention are colorless to pale yellow oils or low me1ting...solids. .The. compounds. having. a hydrogen atom in the 4-position on the piperazine ring (R being hydrogen) are very soluble in or miscible withwater. In other compounds wherein the hydrogen in the 4-positionis replaced by other groups indicated above the water solubility decreases with the I increase in molecular weight of the substituent group-=in-*the;=4-position; "-"-The compoundsin general are" soluble "in" the usual organic. solvents. Salts of the compounds of the present invention may be formed with acids such as -hydrochloric,"citric, sulfuric, hydrobromic, tartaric and the like; Some of these additionr salts are: difficult to isolate as; solids-abecause of their marked hygroscopicity; :others form twellfl defined white -crystal1ine;: h-ydrated: or anhydrous salts. In generalyathe-additiorrzsalts of .the. present compounds may be readilylprepared by adding an anhydrous acid to an; anhydrous solution of rtheodialkylaminoethyl piperazine-lcarboxylate in an organic ether solvent and isolatingthe precipitated salt by filtration. v

The preparation of the new compounds of the present invention may be accomplished in several ways depending to a large extent on the nature of the product desiredi We prefer to prepare the compoundsby heating a piperazine-l-carboxylate having the formula:

RN" N-c-oR" in which R, X and Y are as Adefi-ned :aboveuand ,R f; is lan-lalkiylorr aralryr ag ar itn dialk ylaminolethanoliulthe, presence bf an alkali metal alcoholate. such as sodium or pota ssium diethyl- .aminoeth'ylate. jASiIStarting' material we ean use compounds such asfl l carbethoxypiperazine; {-1- icar bethoxy trans F 2,5 "-f-jdimethylpiperaaine; 1 ,,carbe thoxy -14 methylpiperazine,=- l --'--car- ,bomethoxy -i4 c-.-. methylpiperazine; l -.-carbethvoxy 4 L-i.lben y 'pirer zinc: 1 r thoxy 4-- phenymipenaz nal escar i ben oxypipe az a carbobenzoxylrmethylpiperazineand the like.

As', intrmdiatestQ beireac dwit t e-piperlazine-lr carboxylates we canuse compoun ds such as 2-dimethylaminoethanol, zediethylam-inoethanol, 2 ethylmethylaminoethanol,=2 dipropylaminoethanol, 2 ethylpropylaminoethanol, 2 ldibutylaminoethanol, etc.

.The reaction for preparingthecompounds;v of the. pres ent inventiommaybe earriedtout -inwthe presence loflanuexcess ofthe-dialkylaminoethanol andlanualkali nietalisuch-assodium-or-potassium. 7

It. is believed 'that the alkali metak forms-analjcoholatenwiththe amino alcohoP-which in turn .reactsgwithjthe piperazine-l carboxylates to pro- ,duce,; the.i.-desired 1 compounds iThe reactionris prefrralo1y.v carried. out at a temperature of from 50 C. to C. "Best resultsha-vebeerrpbtained by heating the reaction mixture under-reduced pressure, followed by f-urther heating at atmosneriapressur cl; ne a1ethe ields-o ta n :underalthese nditionstwerensuperi rb thos obtained by atin tnearea tiomm xtu un *reducedzsml s. e at a mgsplie icemessl alone. *nEDhe-cntbhfllllldSgfif lnresentin ent onrmay besisolatectand purified by distillation. flheflesired compounds have boiling points;highen;than any of the starting materials and therefore are easily separated from-the-intermediats used. Redistillationof .the;:;highest bojlir a- V 1 r usually sufficient .to ri -isle; a prpduc of V purity. somelorstheno noundslaof-a helnre en tion,-particularlyelthose having an arallgy cal" in the: 4'epositioni on themip he -prepared: byiaheatingzv a 2.- piperazine':lgcarbvoxylategw a a halogen compound SuChL'flS. benzyl chloride, bro- Example 1 In a flask connectedito a condenser and receiver is placed 817 parts of Z-dimethylaminoethanol, which contains 8 parts of dissolved sodium, and 474 parts of l-carbethoxypiperazine. The mixture is heated first between 60-67 C. for 7 hours at 32-38 mm. pressure and then at 140 C. for? hours at atmospheric pressure. The resultant solution is carefully fractionated at reduced pressure to remove excess 2-dimethylaminoethanol and unreacted l-carbethoxypiperazine. A crude fraction, boiling point 140- 160 C. at 15-25 mm. iscollected and redistilled to. yield Z-dimethylaminoethyl piperazine-l-carboxylate. 'a colorless oil, boiling point 114-11'7 C./0.51 mm., 125 14823.

Eazample 2 'A' mixture consisting of 332 parts of 2-diethylaminoethanol containing 3 parts of dissolved sodium and 186 parts of 1-carbethoxy-'trans-2,5- dimethylpiperazine is heated in a mannerdescribed in Example 2. A colorless oil, 2-diethy1- aminoethyl trans-2,5-dimethylpiperazine-l-carboxylate, boiling point 144-147 C./1 mm., 11. 1.4760'i collected.

Example 4 A mixture of 46 8 parts of Z-diethylaminoethanol containing 4 parts of dissolved sodium and 1'72 parts of 1-carbethoxy-4-methylpiperazine is heated under reduced pressurev and at atmospheric pressure in a manner similar to that described in Example 2. Purified material consists of 2-diethylaminoethyl.4-methylpiperazinel-carboxylate, a colorless oil,.boiling point 127 128 C./1- mm; 11 1.4700.

' Example A mixture consisting of 23 parts of 2-diethylaminoethyl piperazine-l-carboxylate, 25 parts of sodium bicarbonate, 12.7 parts of benzyl chloride and 100 parts of ethyl alcohol is heated under refiuxing conditions for three hours. The inorganic salts present are removed by filtration and the alcoholic filtrate is evaporated under reduced pressure. Water is added to the residue, and the oil that appears is extracted with ether. The ether is dried and treated with hydrogen chloride gas. 'The Z-diethylaminoethyl 4-benzylpiperazine-l-carboxylate dihydrochloride hemihydrate that precipitates is collected and recrystallized from an alcohol-ether solvent to yield a white solid, melting point 194.0195.5 C.

Example 6 A mixture of 234 parts of 2-diethylaminoethanol which contains 2 parts of dissolved sodium and 93.5 parts of l-carbethoxyl-phenylpiperazine i treated in a manner similar to that described in Example 1. The product, 2-diethylaminoethyl 4-phenylpiperazine-1-carboxylate is a pale yellow liquid, boiling point -l78 C./1 mm., 11. 1.5328.

Erample 7 A salt is prepared by passing hydrogen chloride gas into an ethereal solution of-2-diethylaminoethyl 4 methylpiperazine-l-carboxylate. The product, 2 diethylaminoethyl 4 methylpiperazine-l-carboxylate dihydrochloride, is obtained as a white solid which melts after recrystallization from alcohol-ether at 196.3- 198.3 C. with eifervescenoe.

Example 8 A salt is obtained by the addition of hydrogen chloride gas to an ethereal solution of 2-diethylaminoethyl 4 phenylpiperazine-l carboxylate. The white solid obtained in this manner is 2-diethylaminoethyl 4 phenylpiperazine-l-carboxylate dihydrochloride hemihydrate which melts at 161.2-165.2 C. after purification from alcoholether.

I claim:

1. Compounds having the general formula:

in which R is a monocyclic aralkyl radical and R is a lower alkyl radical.

2. Compounds having the general formula:

in which R is a monocyclic aryl radical and R is a lower alkyl radical.

3. 2-diethylaminoethyl trans 2,5 dimethylpiperazine-l-carboxylate.

4. Z-diethylaminoethyl 4 benzylpiperazine-lcarboxylate.

5. Z-diethylaminoethyl 4 phenylpiperazine-lcarboxylate.

6. Compounds of the group consisting of those having the general formula:

in which R is a member of the group consisting of hydrogen, lower alkyl, monoeyclic aralkyl and monocyclic aryl radicals, R is a lower alkyl radical, X and Y are members of the group consisting of hydrogen and lower alkyl radicals and addition salts thereof.

5 6 7. Compounds having the general formula: Number Name Date 2,472,496 Stewart June 7, 1949 0 2,474,651 Blicke June 28, 1949 QMLWCECEMM 2,485,550 Aeschlimann et a1. Oct. 25, 1949 5 FOREIGN PATENTS Y Number Country Date In whwh R X and Y g 35 539,329 Germany May 9, 1930 HAR OTHER REFERENCES REFERENCES CIT 10 Swan et aL: Amer. J. Opthalmology 27, 933-940 The following references are of record in the (1944)- file of this patent: Groggms: Umt Processes 1n Orgamc synthesls, third ed., pp. 635-636 (1947), McGraw-Hill Book UNITED STATES PATENTS 15 CO" Inc" New York, Number Name Date Reid, Ind. Eng. Chem. 40, 1598 (1948).

2,218,739 Bruson Oct. 22, 1940 

6. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE GENERAL FORMULA: 